Breast cancer is a heterogeneous disease which arises due to complex molecular changes. Among various molecular changes, Polycomb group (PcG) proteins are known to be aberrantly expressed during breast cancer progression. In particular, BMI1 and EZH2 are overexpressed in breast cancer cells. The exact role of BMI1 in breast cancer progression is not very well understood. A better understanding of oncogenic activity of BMI1 and its regulation is necessary to define its oncogenic role in breast cancer. The long-term objectives of this proposal are- identify molecular targets of BMI1, study signaling pathways that regulate BMI1 expression, and explore the role of BMI1 in drug resistance in breast cancer cells and breast cancer patients. In aim 1, we will identify molecular mechanisms which regulate expression of BMI1. In particular, we will study posttranslational regulation of BMI1 in normal human mammary epithelial cells and breast cancer cells. We will also identify novel signaling pathways that are involved in BMI1 proteolysis induced by genotoxic drugs in breast cancer cells. In aim 2, we plan to identify potential oncogenic mutations in BMI1 oncogene, which may make it more stable and potent, and study the oncogenic role of mutant BMI1 proteins in breast cancer. In aim 3, we plan to study the oncogenicity of wild type and mutant BMI1 proteins using mouse xenograft studies and identify potential breast cancer-related targets of BMI1 using microarray analysis. In aim 4, we plan to study the role of BMI1 in chemoresistance in breast cancer patients. Successful outcome of the proposed studies will help in understanding the role of BMI1-regulated and BMI1 regulating pathways which could be targeted for breast cancer therapy. A clear understanding of signaling pathways regulating BMI1 expression will also help in developing breast cancer therapies that target BMI1 and BMI1 containing PcG complexes which are dysregulated in breast cancer. PUBLIC HEALTH RELEVANCE: The proposed studies will help understand the role of Polycomb Group protein BMI1 in cancer development, progression and treatment. These studies will help in developing breast cancer therapies that could target BMI1 expression to halt breast cancer progression.